Lyme disease is a multisystem illness caused by infection with the spirochete Borrelia burgdorferi and it is the leading vector-borne disease in the United States. Lyme disease is also common in Europe (mainly middle Europe and Scandinavia) and also occurs in Russia, China and Japan. In humans, B. burgdorferi infection causes infection primarily in the skin, nervous system, heart and joints. Lyme disease can usually be treated successfully with antibiotic therapy, with the best results seen in patients with early disease. Unfortunately, some patients may not have a complete response to therapy. The mechanism(s) underlying persistent signs and symptoms of disease, despite the administration of what is currently considered to be adequate antibiotic therapy, is one of the most controversial issues regarding Lyme disease today. This syndrome of nonspecific symptoms has been named post-treatment Lyme disease syndrome (PTLDS). We currently have two clinical protocols studying patients with Lyme disease. Both protocols are natural history studies and serve as the basis for multiple lines of investigation. One protocols addresses patients with PTLDS as well as controls, including patients with Lyme arthritis, individuals who recovered from Lyme disease, individuals found to be seropositive but who are asymptomatic, individuals vaccinated with the OspA vaccine, as well as healthy volunteers and patients with multiple sclerosis. The other protocol allow for the study of patients with classical Lyme disease. Regarding laboratory diagnostics, we have focused in developing better tests for both diagnosis and for persistence of infection. We have collaborated with Dr. Mario Philipp and his group at Tulane University Medical Center, in the development of the C6 peptide ELISA. This test is simple to perform and is highly sensitive and specific. An important advantage of this test is that it can be used to diagnose Lyme disease in patients who have received the Lyme disease vaccine, and it can be used in Europe, where Lyme disease may be caused by B. garinii and B. afzelli. Besides the use of the C6 antibody response for diagnosis of Lyme disease, we are currently evaluating this response as a possible marker for clearance of infection. In collaboration with Dr. Roland Martin (Neuroimmunology Branch, NINDS), we are studying the specificity repertoires and function of Borrelia burgdorferi-specific T cell clones using a novel methodology to decrypt the antigen specificity of T cell clones. This methodology uses positional scanning synthetic combinatorial peptide libraries and biometric score matrices and it is a powerful new tool to investigate what role autoimmune mechanisms play in the development of chronic symptoms associated with Lyme disease as well as to study other infectious and immunologic diseases. In follow up to these studies, we developed a highly specific and sensitive technique to track single T cell clones. T cell clonotype tracking enables to further elucidate the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses. We have investigated the patterns of magnetic resonance (MR) abnormalities in our cohort of patients with PTLDS. We used the sensitive fluid-attenuated inversion recovery (FLAIR) sequence in addition to T2-weighted fast spin echo (FSE) imaging to increase the potential yield of white-matter lesions. We also employed magnetization transfer ratio (MTR) histogram analysis of the whole brain in a subgroup of patients with PTLDS to test for diffuse structural abnormalities of the brain parenchyma, potentially resulting from demyelination or inflammation. We found that a portion of patients with PTLDS had white-matter hyperintensities, which tend to occur in subcortical arteriolar watershed areas and are not specific. Magnetization transfer ratio analysis did not provide evidence for structural abnormalities of the brain parenchyma in patients with nonfocal disease. Together with NINDS and the ORD, we convened a workshop to evaluate the current knowledge in neurologic Lyme disease. Participants included researchers from the fields of infectious diseases, neurology, rheumatology, basic immunology and autoimmune disease, largely but not exclusively focused on Lyme disease. The main purpose of this workshop was to evaluate the current state of art in diagnosis, treatment and follow up of neuroborreliosis in the US, and to facilitate research by bringing together scientists in the field in an environment supportive for the presentation and discussion of cutting edge research.